Nu-oxyalkyl-p-aminobenzoate compounds



Patented Apr. 28, 1953 N- OXYALKYLP-AMINOBENZOATE COMPOUNDS David I. Weisblat and Barney J. Magerlein, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan NoDrawing. Application August 19, 1950, Serial No. 180,501

-- I -15, Claims.

1 v The invention relates to new N-oxyalkyl-paminobenzoate compounds, particularly to such compounds wherein the oxyalkyl group is a 2-oxypropyl group which may or may not have an alkyl substituent on the third carbon atom thereof, and to a method useful in their preparation.

The N-oxyalkyl-p-aminobenzoate compounds of the invention have the generic formula COOR I N-oxyalkyl-p-aminobenzoate compound wherein R is a member of the class consisting of hydrogen and the alkyl radicals, n is a member of the class consisting of zero and the positive integers 1 to '7, inclusive, Z is a member of the class consisting of hydrogen and the arylsulfonyl radicals, R is a member of the class consisting of. hydrogen and the alkyl radicals and Y is a member of the class consisting of radicals having the formulae --CHOH- and -CO-. The new compounds of the invention thus include the N-(2-hydroxyalkyl) p-aminobenzoate ester compounds having the Formula IV given hereinafter and the corresponding acids and also the N-(2-ketoalkyl) p aminobenzoate compounds having the Formulae V and VI.

In the naming of the compounds of the in vention, and of other compounds mentioned herein, when both a glutamic acid residue and a p-aminobenzoic acid residue are included in the molecule, the nitrogen atom of the glutamic acid residue is, for convenience, herein referred to by the symbol N and the nitrogen atom-of the p-aminobenzoic acid residue is referred to by the symbol N. As indicated in the generic formula given, compounds containing more than ,one glutamic acid or ester residue contemplated by the invention are those wherein only the gamma carboxyl groups are involved in the peptide linkages. Preferred compounds, however, are those wherein n of the generic Formula I is the integer 1.

Compounds having the generic Formula I given above are useful as intermediates in the preparation of compounds similar to or identical with certain naturally occurring compounds of the folic acid group. Thus, as described and claimed in concurrently filed copending application, Serial No. 180,509, diethyl N'-(N-(2-ketopropyl) N (p toluenesulfonyl) p aminobenzoyl)- (pteroylglutamic acid) when the glutamic acid residue has the same configuration as '1 (-1-) glutamic acid, as being identithe folic acid type.

to form diethyl N'-(N-(2-formyl-2-ketoethyl)- N (p toluenesulfonyl) p aminobenzoyl)- glutamate which can in turn be condensed with 2,4,5-triamino-6-hydroxypyrimidine as described and claimed in copending application, Serial No. 63,454, filed December 3, 1948, to form diethyl N'-(N-((2 amino 4 hydroxy 6 pteridy1)- methyl) -N-(p-toluenesulfonyl) p aminobenzoyl) -glutamate. The latter compound upon treatment with anhydrous hydrogen bromide in an aliphatic acid medium, and in the presence of a bromine acceptor to prevent bromination .of the benzene nucleus of the p-aminobenzoic acid residue according to the method described and claimed in copending application, Serial No. 41,883, filed July 31, 1948, and after subsequent hydrolysis of the ester groups, is converted to N'-(N-((2-amino 4 hydroxy 6 pteridyl)- methyl) p aminobenzoyl) glutamic acid generally recognized,

cal with the L. casei factor, or vitamin Bo from liver, sometimes referred to as folic acid. When N (N-(2-formyl-2-ketoethyl) p aminobenzoyD-glutamic acid is condensed with 2 4,5-triamino 6 hydroxypyrimidine, pteroylglutamic acid is formed directly without the necessity of splitting the toluenesulfonyl radical from the product or of hydrolyzing ester groups. In similar fashion other N-(Z-ketoalkyl)-p-aminobenzoate compounds wherein Z of the formula given is an arylsulfonyl radical can be oxidized and the product condensed with 2,4,5-triamino-6-hydroxypyrimidine to form other compounds of The N- (2-hydroxyalkyl) -paminobenzoate compounds are, as is herein described, useful in the preparation of the N-(2- ketoalkyl) p aminobenzoate compounds and hence of the above mentioned folic acid compounds.

Compounds of the generic formula previously given wherein Z represents an arylsulfonyl radical are preferred compounds of the invention and are of particular value because of the protection afforded the aromatic amino group by the arylsulfonyl group. Compounds having the amino group thus protected are not as subject to decomposition and the formation of by-products when employed as a reactant, e. g. when the hydroxy compounds are oxidized with chromic acid and when the keto compounds are condensed with 2,4,5-triamino-6-hydroxypyrimidine, to nearly 'the'same "extent as are compounds in glutamate can be oxidized with selenium dioxide 5 which the arom ic amin roup is pr t Although the invention is described in the case of the arylsulfonyl compounds with particular reference to p-toluenesulfonyl compounds, it is to be understood that the invention contem plates compounds "and intermediates 'con'taining other arylsulfonyl radicals, such as -the-o-tolue11esulfonyl, benzenesulfonyl, and naphthalenesulfonyl radicals as well as many others. Arylsu'lfonyl radicals having substituents, such .as schlorine, bromine or nitro groups and others, .on the aromatic nucleus can also be used, provided only that the substituent isinon-rreactiwa :under the reaction conditions. lt-should bezmentioned that the method involved 'in'the 'presentdnvention can be carried out and the corresponding intermediate and final compounds prepared using starting compounds wherein the arylsulfonyl group is replaced by an alkylsulfonyl, aralkylsulfonyl, or cycloalkylsulfonyl group such 'asthe methanesulfonyl, alpha-toluenesulfonyl or cyclohexysixlfonyl "radicals, respectively.

:A preferre'd 'arylsulfonyl 'radical is l the p-to'l- :uenesulfonyl "radical Ibecause 'ithe compounds forme'd: are generally well-defined crystallinessnlids and because it has ibeen found that rhigher yields 'of amines 1 are often "formed when the ;ptoluenesulfonylam'ino :eompound 11S split ithan when certain other larylsulfonyl "derivatives vo'f the sa-me arninocompound. are split.

Although aming benzoic ra'ci'd 'ester ror fglntam'io :3

acid estenresiduespresent inthe:estencompounds prepared by "the :method :of the invention ican comprise an alkykester, suchastthe methyl, :ethyl, npropyl, iso-propyl, nbutyl, tert.-'bu'ty1, .amyl,

'laur-yl, dodecyl andzma-ny nO'thBralky l sesterstthe 7 preferred esters are those having less than *8 carbon :atoms in the -a1ky1 "radical, particularly the ethyl ester, Jdue "to matters rof "convenience and economy.

Although the invention is:direote'd gparticulai'ly *to a1ky1 esters, "theprocess of the invention can "also be-"oarried out and the :corresponding compounds prepared using other'esters,:such as the phenyl, tolyl, xylyl,:'cyclohexyl, benzylcand many other and, "aralkyl .or cycloalkyl :esters.

Although the invention will :be described "with particulanreference'to compounds containing the 2-oxypropyl radical, it is '1 to :be understood that compounds containing other' 2-oxyalk-yl radicals, such as the E- ketobutyl,'2 hydroxybutylf2 keto- 'pentyl, "2-=hydroxypentyl, Z-ketoheptyl, "i2-hydroxyheptyl radicals and othersgareaLlso included :withinthe scope ofthe'iinventi'on. "The-preferred compounds are, however, the "N-(2=hydroxypropyl) p aminobenzoate 'compounds an'd theN- 62 -ketopropyl) --*p aniinobenzoatescompourids previously mentioned.

R-IIHz-tOH-:CH2

Epozyalkane I rojotoau l 'HNQC'O Nn'o 11011201150 o )no min! :p-aminohenzoatesester-zcomponnd IV N(Z-hydroxyalkyl)-p-aminobenzoate ester compound Oxidation (with or without hydrolysis before or after oxidation step) (when Z=aryl 5.02

I R-CHzC O CHz-ITI-OC O (NHCHCHzCHzC 0),,OR

COOR

' I rnaongoonntnnfgo 0 (NHCHC HzCHzCO no R VI lN-f('2 -ietoalkyl)-p-aminrgbergoate compound wherein .The -N-oxya1kyl-p1aminobenzoate compounds ((1) roan he prepared readily, :as iindicatedlin the accompanying reaction .chart wherein 5R1, m, 32, .rRand ,3? have theivalues previoiww given,3hy.-ro-

J acting an epoxyalkane having :the .Formula :II .with a ;p-aminohenzoate iester compound 'having the Formula III to form an l l-(2-hydroxyalk;y1)-- p-aminobenzoate lester; compound (1V0 .of theiinvention. .-An N-.(2ehydroxyalkyl)- p1aminohenzoate compound .(IV) in which Z is hydrogen can be converted readily to its arylsulfonyl derivative, i. e. to an 'N-(2-hydroxyal1 :yl)- p-aminobenzoate compounds (IV) 'in'which Z is an arylsulfonyl radical by reaction with an arylsulfonyl halide in .conventionalmanner. lAlso the aryl- ,sulfonyl compounds can be converted readily to the correspondingr'free aminesby treatmentwith hydrogen bromide "according to 'the "method of the :copendingxapplicationpreviously:referredito. :Alkyl testers having the .Formula IV can lbei'hY- 'drolyzed readily tothe corresponding acids with 'dilutealkah.

Oxidation 'of an N"(2-h ydroxya1ky1) -p-amino- 'benzoate "ester compound .1(IV),,or of the corre- Vsponding acid, wherein z'istan'arylsulfonyl radica'l, preferably with "a chromic compound, i. :e. with chromic 'anhy'dride 'or' with an acid solution ofra dichromate, converts the CIIOH-"group smoothly "to a --CO- group'with the formation of an 'N-( ketoalky1) p aminobenzoate compound (V) wherein Z'is an arylsu'lfonyl radical. Thellatter compound can .be converted readily with -jhydrogen bromide by the method of the 'copending :application previously mentioned 'to :the free amine, i. :e. :to an LN-TZ-ketOaIkyD paminobenzoate compound '(V'I) xwhereimzisrhyfdrogen.

Epozgyalkanes '(II) which :can be used in the process of theinvention :are the "1,2-epoxypro- 'panes 'and the l',2-'epoxy 3-al1-;ylpropanes, :e. the "substituted lZZ-epoxypropanes wherein the substituent ;is an alkyl .radical "attached 'to the 'third carbon atom of the propane carbon chain. Epoxyalkanes which can be "used in the process include, among others, 1,2-epoxy propan'e, 'l,'2- epoxy ii methyl-propane, 1,2-epoxy-3-ethYl-5propane, -1,2-epoxy-3:propyhpropane .1;2-'epoxy-3- isopropyl propane sand 1.,2-epoxy-i3-tertiarybutyl 'propane. The preferred epoxyalkane is J,,'2-epoxypro1oane.

.Among the p-aminobenzoate compounds '(III) which can be usediin 'thepro'cess of th-einvention 'areiincluded ethyl p-aminobenzoate, fdiethyl N-'(p-aminobenzoy1) -glutamate, triethyl 'N'-'(paminobenzoyl) glutamyl glutamate, their 1N- arylsulfonyl derivatives and many others.

'nitrobenzoyD-glutamic acid or ester is first obtained which, upon reduction, e. g. with hydrogen using platinum oxide as a catalyst, yields an N- (p-aminobenzoyl)-glutamic acid or ester. The latter compound can be converted readily by means of an arylsulfonyl halide to an N-(N- (arylsulfonyl) -p-aminobenzoyl) -glutamic acid or ester. When an arylsulfonyl-p-aminobenzoyl halide is reacted with glutamic acid or its ester,

an N (N- (arylsulfonyl) -p-amin-obenzoyl) -glutamic acid or ester is formed directly. The N'- (p-aminobenzoyl) -glutamic acid and the N'-(N- (arylsulfonyl) -paminobenzoyl) -glutamic acids can be converted to the corresponding alkyl esters, e. g. by treatment with an alkanol and an esterification catalyst. In similar manner, other p-aminobenzoate compounds can be prepared having up to seven glutamic acid residues in the molecule by starting with the corresponding gamma-glutamyl-glutamic acids or esters containing the requisite number of peptide linkages.

The reaction of an epoxyalkane with a paminobenzoate ester compound (III) is carried out conveniently by heating a mixture of the compounds containing a catalytic proportion, usually about 2 per cent or somewhat less of the weight of the mixture, of a. tertiary amine, such as pyridine, quinoline, triethylamine, tributylamine and the like. Heating is usually carried out at from about 80 C. to about 150 C. for from a few minutes to a few hours or longer, although the degree and time of heating are not critical other than to assure substantial progression of the reaction. The reaction proceeds smoothly and without the formation of undue amounts of by-products. Inert diluents can be employed, if desired, although they are not usually necessary.

When a low boiling constituent is present in the reaction mixture the heating can be carried out under pressure if desired.

Following the heating step, the entire reaction mixture can be diluted with benzene, ether or other suitable solvent for the NflZ-hydroxyalkyl) -p-aminobenz'oate ester compound and the solution washed with dilute mineral acid to remove the tertiary amine. The washed solution can then be dried, e. g. with anhydrous sodium sulfate or by distilling to remove water, and the solvent evaporated to obtain the N-(Z-hydroxyalkyD-p-aminobenzoate ester compound as a residue which is generally oily in nature. The ester is hydrolyzed readily by stirring it with dilute alcoholic alkali until it dissolves, acidifying the solution and collecting and drying the precipitated acid. The acids are often crystalline. The N-(2-hydroxyalkyl) -p-a1 ninobenzoate compounds are generally thus obtained in a form sufilciently pure for further use but they can be purified further if desired either by chromatography or by crystallization from alcohol or from a mixture of ether and hexane, or in any other convenient way.

aminobenzoate compound wherein Z in the formula given is an arylsulfonyl radical, and wherein the compound is either an ester or the free acid, can be carried out conveniently by dissolving the hydroxyalkyl compound and chromic anhydride in glacial acetic acid or other suitable solvent and allowing the mixture to stand for several hours at about room temperature or somewhat below, preferably with gentle agitation. The mixture which is formed generally consists of a liquid and a solid portion from which the N (2 ketoalkyl) p aminobenzoate compound can be recovered in any convenient way, e. g. by stirring the mixture with ether and filtering or by diluting with water and extracting with benzene or ethyl acetate. In either case a solution of the ketoalkyl compound in an organic liquid is obtained which can be washed free of inorganic salts and water-soluble acids and then dried and the solvent distilled under reduced pressure. The N-(2-ketoalkyD-p-aminobenzoate compound is thus obtained as a yellowish sirupy or solid residue depending, generally, upon whether it is an ester or a free acid. Oxidation of an N-(2-hydroxyalkyl)-p-aminobenzoate compound wherein Z of the formula given is hydrogen yields the corresponding 2- ketoalkyl compound in very low yield.

The oxidation can also be carried out in accordance with the method described and claimed in. concurrently filed, copending application Serial No. 180,507, by agitating a solution of an N- (2-hydroxyalkyl) -p-aminobenzoate compound wherein Z in the formula given is an arylsulfonyl radical in a suitable water-insoluble organic liquid with an oxidizing mixture of potassium dichromate, acetic acid, water and sulfuric acid at room temperature for several hours and subsequently separating and washing the organic layei and recovering the product as before.

In certain instances, an oily N-(2-ketoalkyl)- p-aminobenzoate compound obtained in the manner just described can be obtained in partially crystalline form by allowing it to stand for several hours. In certain instances it may be desirable to purify the ketoalkyl compound e. g. by preparation and crystallization of a crystalline derivative, such as the semicarbazone, from which the ketoalkyl compound can later be recovered in conventional manner. The crude product obtained from the oxidation mixture,

can, however, generally be used without further purification in subsequent reactions. Gentle alkaline hydrolysis of the N-(2-ketoalkyD-paminobenzoate compounds, e. g. with cold aqueous or alcoholic allrali, leads to the formation of the free acid which can be recovered from the alkaline solution in a somewhat oily or solid yellowish form by acidification. The ketoalkyl compounds which are solids can be recrystallized from alcohol.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

Example 1.--Diethyl N" (N (p toluenesul fon yi) p aminobenzoyi) glutamate Thirty and nine-tenths grams of p-toluenesulfonyl-p-aminobenzoyl chloride and 23.9 grams of diethyl 1(+) -glutamate hydrochloride were dissolved in 300 milliliters of ethylene dichloride and the solution cooled to between 0 and 10 C. The cold solution was stirred vigorously and 22.3 grams of triethylamine in '72 milliliters of ethylens dichloride was :added slowly over :a ,period of about2Dzminutes. Zllhe temperature of the mixiture was :held between .andi2ll (C. :during the addition of the triethylam'ine and the mixture then allowed to stand at -room temperature for one liour. The mixture was then washed successively with 'water, :dilute hydrochloric acid, saturatedaqueousxsodium"bicarbonate and finally with water. The colorless solution thus obtained was dried with anhydrous sodium sulfate :and naphtha was added until the solution became opalescent. The mixture was then cooled to cause crystallization :and filtered. The crystals, after drying consisted of 36 grams :of diethyl N--? '('N- '-(=p :toluenesulfonyl) p arn'inobenzoyl) 1- iglu'tamate melting at 1243 to I ('3.

Example 2.--Diethyl .(N (2 .sH-ydroxy- :mopylo N "(ptoluenesulfonyl) -41 amino- Fbcneoyll glutamate 5A mixture .of 6.38 grams col propylene pxide, 4.7.1.7 grams of riieth l .N' fi'N-zip-toluenesulfonyl .peaminobenzoyll-glutamate :10 drops :of anhydrous pyridine "was heated under pressure at 1 113N132 for 12 hours. Theyreaction mixture'ivas then cooled to room temperature, .400 imilliliters of benzene were addedandathe resulting benzene solution was washed with '50 milliliters of Water and milliliters of .dilute hydrochloric acid and then dried. Removal of thesolven't underreduced pressure gave a non crystalline solid residue of diethyl N' -dNfiz-hydroxypropyb -.-NL(p-'t,oluene- 'sulfonyl l.psminobenzoyl) 'lutama'te.

lo a similar :manner, and using lgz-epoxy-n- I hut-sneer 1,l-epoxy-emethylen pentane in place of 1,2-epoxypropane, there :are Jformed :diethyl 'N N.- ft2.- :hydroxy-n Abutyl) .-N ftp atoluenesulfonyl) -p aminobenzoyl) glutamate n pentyl l N (p toluenesulfonyl) -=.p--.amin0 'benzoyl) g'luta1nate, respectively, which upon hydrolysis, give the corresponding acids.

The-use of ethyl N-(benzenesulfonyl) -p-amino- 'benzoate or of triethyl N '-'(N-'(p-chlordbenzene sulfon-yl-l p am'inobenzoyl) -'glutamy1 glutamate in "place of diethyl N-(N-(p-toluenesulfonyl) 13 aminobenzoyl) glutamate leads, in analogous manner, to the formation of ethyl N- '(2 -1hydroxy.propyl) N .(benzenesulfonyl) -'paminobenzoate and triethyl -N-(N502=h ydroxvnropyl) .N p vchlorobenzenesul'ionyl) paminobenzoyl) .glutamyl glutamate, respec tively. The latter two esters, upon hydrolysis with dilute alcoholic sodiumhydroxide,.are converted toN (2 hydroxypropyjl) -'N "(benzenesulionyl) p am'ino'benzoic acidand N (N- (2 --rhydroxypropyl) 'll (p chlorobenzenesulionyl) p -.amin,obenzo yl') glutamyl 'glutamic acid, respectively. The free acids mentioned, upon esterification withanalkanol or with other a-liqyl ester-forming agents, are converted to the corresponding .alkyl esters.

Upon treating the Z-hydroxyalkyl compounds mentioned which are arylsulfonyl derivatives with hydrogen bromide according to the procedure described in the copending application previously referred to, :the arylsulfonyl radical is split from the molecule leavlngthe corresponding '2 hydroxy alkylamino compound. The latter, upon reaction with an 'arylsulfonyl halide in substantially conventional fashion, are converted readily to the corresponding arylsulfony1 derivatives of the amine.

Example (as-mim c! 1N AN 3( 2 lketm mfifl N 1611 -.ito.luenesulfonyl-) ---,p aminabenzozlllglu'tamate The crude methyl IN'-I(N'(2ehydroxypmpyl)- .N '(p ito'luenesul'tonyl) p aminobenzoyhlutamate ObtainedinExampleZ was dissolved'in 1 milliliters of benzene and the solution was added with vigorous stirring .to a solution .consisting 01552.6 gramsof potassium-dichromate,.230 milliliters .of water, 38 milliliters of acetic acid and '69,.milliliters of sulfuric acid. The mixture wasstirred vigorously .at 20 to 25 .C.. for about 2 hours, cooled and the benzene and aqueous layers se arated. The aqueous layer was .ex- .tracted .twice with ,1 Oil-milliliter portions of henzone and .then discarded, the ,benzene extracts being added to the benzene layerfrom the reaction mixture. The combined benzene solutions were washed three ,times with 250-milliliter por tions of water, ,once'ivith 100 milliliters .of saturated aqueous sodiumbicarhonatesolution, twice with .zfio-milliliter portions of water and .once with 10.0 milliliters .of saturated aqueous sodium chloride solution. The washed benzene solution was then dried and the solvent distilled under reduced pressure. ,The residue was dissolved in .hot .iso-propanol and the solution .allowed .to crystallize at room temperature. The mixture was filtered and the crystals dried. There were thus obtained 34.5.grams of crude diethyl l-l'.-(N- (2 ketopropyl) m .N .(p toluenesu'lfonyl) -,p aminobenzoyl.)-glutamate which melted .at .88" to C. Recrystallization of the'crude'ketone raisedits melting point to 9.9 110,125 .C. Incn alternate procedure, diethyl I\T' -(N- (Z-hydroxypropyl) ll ,(p toluenesulfonyl) p amino- .henzoyll-glutamate .and a .small excess .over .the theoretical amount of chromic anhydride are dissolved in glacial acetic acid and the mixture allcwedto stand for several hours with-occasional agitation-at-about 5 to 10C. The ,mixture .is then stirred with ether and filtered. The ethereal solution is washed with water and aqueous .bicarbonate, dried and the ether evaporated under reduced pressure. Diethyl N-(1 T CZ-Ketopropyl) 1N -(p -.toluenesu1fonyl-) p --a1ninoben- 'zoyl) -glutamate :is thus obtained as a yellowish viscous residue which can be purified as .pre- Niously described.

A solution of 31.0 grams of crude diethyl N'- (N -(2 ketopropyl) N -(p--.toluenesulfony1)-- paminobenzoyD-glutamate, 11.1 grams :of semicarbazide hydrochloride and-9.0 grams of sodium acetate in :a mixture of 209 milliliters -.of ethanol .-and.50: mi11iliters of water was heated :under re- .fiux {or '2 hours, cooled and diluted with water.

Anal:

Calcd. for CzvHssNsOsS: C, 54.9; H, 5.98; N,

11.9. Found: C, 55.0; I-I, 6:27; N, 11.6.

,A mixture of 18:2 grams .of :the semicarhazone of diethyl N--(N-(2-ketoprop;il)eN-l-p-toluenc sulfonyl) -p-aminohenzoyll-glutamate, l5 milliliters ofbenzene, '35 milliliters .of ethanol, 7'85 mil-- liliters of water and 17 milliliters of concentrated aqueous hydrochloric acid was heated under. :re-

flux for 2 hours. The organic water-insoluble layer was separated and washed twice with equal volumes of water, once with an equal volume of saturated aqueous sodium bicarbonate solution and once with an equal volume of saturated aqueous sodium chloride solution and then dried. Upon distilling the benzene under reduced pressure, an oily residue was obtained which was recrystallized from iso-propyl alcohol. There were thus obtained 13.6 grams of pure diethyl N-(N- (Z-ketopropyl) -N- (p-toluenesulfonyl) p aminobenzoyl) -glutamate melting at 103 to 106 C.

Oxidation in a similar manner of diethyl N'- (N- (2-hydroxy-n-butyl) -N- (p toluenesulfonyl) p-aminobenzoyl) -glutamate, diethyl N- (N- (2- hydroxy 4 methyl-n-pentyl) -N-(p-toluenesu1- fonyD-p-aminobenzoyl)-glutamate, N (N (2- hydroxy n butyl) N (p-toluenesulfonyl) -paminobenzoyD-glutamic acid, N-(Z-hydroxypropyl) -N-(benzenesulfonyli -p aminobenzoic acid, ethyl N- (2-hydroxypropyl) -N- (benzenesulfonyl) p-aminobenzoate, triethyl N (N (2 hydroxypropyl) -N-(p chlorobenzenesulfonyl) -p-aminobenzoyl) -glutamyl-glutamate and N- (N- (2-hydroxypropyl) N (p chlorotoluenesulfonyl) -paminobenzoyl)-glutamyl-glutamic acid gives diethyl N (N-(2-keto-n-butyl)-N-(p-toluenesulfonyl)-p-aminobenzoyl)-glutamate, diethyl N- (N-(2-keto-4-methyl-n-pentyl) N (p-toluenesulfonyl) -p-aminobenzoyl) -glutamate, N- (N- (2- keto-n-butyl) N (p toluenesulfonyl) -p-aminbenzoyl) glutamic acid, N (2 ketopropyl) -N- (benzenesulfonyl) p aminobenzoic acid, ethyl N-(2-ketopropyl) -N- (benzenesulfonyl) -p-aminobenzoate, triethyl N'-(N-(2-ketopropyl)-N-(p-- chlorobenzenesulfonyl) p aminobenzoyl) -glutamyl-glutamate and N- (N- (2-ketopropyl) -N- (p-chlorotoluenesulfonyl) -p-aminobenz0yl) -glutamyl-glutamic acid, respectively.

Example 4.--Diethyl N (N (2 ketopropyl) -paminobenzoyl) -glutamate A mixture consisting of about 0.5 gram of diethyl N (N-(Z-ketopropyl)-N-(p-toluenesulfonyl) p aminobenzoyl-glutamate, 0.235 gram of phenol and 5 milliliters of a 25 per cent solution of hydrogen bromide in glacial acetic acid is prepared and allowed to stand at room temperature for about 2 hours and then poured into 35 milliliters of dry ether. The mixture is filtered and the residue washed with dry ether and then dried. There is thus obtained a residue of diethyl N- (N- (2-ketopropyl) p aminobenzoyl) -glutamate hydrobromide. Upon stirring the compound with aqueous sodium bicarbonate solution, extracting the mixture with benzene, drying the benzene extract and evaporating the benzene, there is obtained an oily residue of diethyl N -(N-(2ketopropyl) -p-aminobenzoyl) -glutamate which forms a solid semicarbazone.

In a similar manner the arylsulfonyl radical is split from diethyl N-(N-(2-keto-n-butyl)-N-(ptoluenesulfonyl) -p-aminobenzoyl) -glutamate, diethyl N (N-(Z-ketol-methyl-n-pentyl)-N-(ptoluenesulfonyl) p aminobenzoyl) glutamate, N (N- (2-keto-n-butyl) N- (p-toluenesulfonyl) p-aminobenzoyD-glutamic acid, N-(Z-ketopropyl) -N-(benzenesulfonyl -p aminobenzoic acid, ethyl N (Z-ketopropyl)-N-(benzenesu1fonyl)-p aminobenzoate, N-(N- (2 ketopropyl) N (pchlorobenzenesulfonyl) p aminobenzoyD-glutamyl-glutamic acid and triethyl N-(N-(2-ketopropyl) -N--(p-chlorobenzenesulfonyl) -p aminobenzoyl)-glutamy1-g1utamate to form diethy1N- (N-(2-keto-n-butyl) p aminobenzoyl) glutamate, diethyl N- (N- (2-keto-4-methyl-n-pentyl) p-aminobenzoyl)-glutamate, N (N (2-keto-nbutyl) p-aminobenzoyl) -glutamic acid, N (2- ketopropyl) -p-aminobenzoic acid, ethyl N-(2- ketopropyl) p aminobenzoate, N (N-(2-ketopropyl)-p aminobenzoyl) glutamyl glutamic acid and triethyl N (N- (Z-ketopropyl) -p-aminobenzoyl) glutamyl-glutamate, respectively.

In a similar manner, also, the arylsulfonyl radical is split from diethyl N- (N- (Z-hydroxy-n-butyl) -N- (p toluene sulfonyl) -p-aminobenzoyl) glutamate, diethyl N-(N-(2-hydroxy-4-methyln-pentyl) -N-(p-toluenesulfony1) p aminobenzoyl) -glutamate, N- (N (Z-hydroxy-n-butyl) -N- (p-toluenesulfonyl)-p-aminobenzoyl) glutamic acid, N- (Z-hydroxypropyl) -N- (benzenesulfonyl) p-aminobenzoic acid, ethyl N- (2-hydroxypropyl) N-(benzenesulfonyl) p aminobenzoate, N-(N- (Z-hydroxypropyl) N (p chlorobenzenesulfonyl) -p-aminobenzoyl) glutamyl glutamic acid and triethyl N (N (2 hydroxypropyl) -N-(pchlorobenzenesulfonyl) p aminobenzoyl)-glutamyl-glutamate to form diethyl N'(N-(2-hydroxy-n-butyl) -p-aminobenzoyl -glutamate, diethyl N (N-(2-hydroxy-4-methyl-n-pentyl)-paminobenzoyl) -glutamate, N'- (N- (Z-hydroxy-nbutyl) -p-an1inobenzoyl) -glutamic acid, N- (2-hydroxypropyl)-p-aminobenzoic acid, ethyl N-(2- hydroxypropyl) -p-aminobenzoate, N (N- (2-hydroxypropyl) p aminobenzoyl) -g1utamyl-g1utamic acid and triethyl N'(N-(2hydroxypropyl) p aminobenzoyl) -glutamyl-glutamate, respectively.

We claim:

1. Th method which includes reacting a compoundhaving the formula RCH2.-CE/-CH2 wherein R is a member of the class consisting of hydrogen and the alkyl radicals with a compound having the formula C O Oalkyl R, n and Z having the values given.

2. The method of claim 1 wherein R is hydrogen.

3. The method of claim 1 wherein n is the integer 1.

4. The method of claim 1 wherein Z is hydrogen.

5. The method of claim 1 wherein Z is an arylsulfonyl radical.

6. The method of claim 1 wherein Z is the p-toluenesulfonyl radical.

7. The method of claim 1 wherein the reaction is carried out with the aid of a catalytic amount of a tertiary amine.

8. The method which includes reacting a compound having the formula 1 1 wherein R is selected from the class consisting of hydrogen and the alkyl radicals with a compound having the formula COOalkyl 1 11-01120 0 clan-n00 omncncmomc o).0a1k 1 aryl SO:

R and 11 having the values given.

9. The method of claim 8 wherein the arylsulfonyl radical is the -p-toluenesulfonyl radical.

10. The method of claim 8 wherein the chromic compound is chromic anhydride and the reaction medium is acetic acid.

.11. The method which includes reacting a compound having the formula wherein R is selected from the class consisting of hydrogen and the alkyl radicals with a compound having the formula COOalkyl aryl 402 wherein n is a member of the class consisting of zero and the positive integer 1 to form an hydroxyalkyl ester having the formula ooomk l n-omononom-NGoo Nncncmcmc 0)n0 alkyl aryl S02 subsequently oxidizing the hydroxyalkyl ester with a chromic compound in a substantially entirely organic reaction medium to form predominantly a ketoalkyl ester having the formula C O Oalkyl R-CHzCOCHrNGC omrrcnomcmc oino alkyl aryl SO:

and hydrolyzing the ketoalkyl ester to form a ketoalkyl acid having the formula coon R-cmo o 011F360 omnonomomcohon R and 11 having the values given.

12. The method which includes reacting a compound having the formula wherein R is selected from the class consisting of hydrogen and the alkyl radicals with a compound having the formula COOalkyl 12m CO(NH!HCH;CHzO0),Oalkyl aryl 40;

wherein n is a member of the class consisting of zero and the positive integer 1 to form an hydroxyalkyl ester having the formula COOalkyl R-CHzCHOHCHrN-OC0(NH( JHCH1CH-;CO),.0alkyl aryl B02 hydrolyzing the hydroxyalkyl ester to the free acid and oxidizing the acid with a chromic compound in a substantially entirely organic reaction medium to form predominantly a ketoalkyl acid having the formula R-cmo o onr-i goomnonomcmo once aryl S0:

R and n having the values given.

13. A compound having the formula coon wherein R is a member of the class consisting of hydrogen and the alkyl radicals, n is a member of the class consisting of zero and the positive integer 1. Z is a member of the class consisting of hydrogen and the arylsulfonyl radicals, R

is a member of the class consisting of hydrogen and the alkyl radicals and Y is a member of the class consisting of radicals having the formulae --CHOH and -CO.

14. Diethyl N- (N -(2 hydroxypropyl) -N-(ptoluenesulfonyl) -p-aminobenzoyl) -glutamate.

15. Diethyl N-(N-(2 ketopropyl) -N-(p-toluenesulfonyl) -p-aminobenzoyl) -glutamate.

DAVID I. WEISBLAT. BARNEY J. MAGERLEIN.

No references cited. 

1. THE METHOD WHICH INCLUDES REACTING A COMPOUND HAVING THE FORMULA 